Brief Report| Volume 64, ISSUE 12, P1097-1100, December 15, 2008

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Double-Blind, Placebo-Controlled, Multicenter Trial of a Vasopressin V2-Receptor Antagonist in Patients with Schizophrenia and Hyponatremia


      Hyponatremia (serum sodium [Na+] concentration <136 mmol/L) is a prevalent and potentially life-threatening medical comorbidity for schizophrenic patients. No definitive pharmacological treatments have been established. Tolvaptan (OPC-41061), an oral non-peptide V2-receptor antagonist, was recently shown to correct hyponatremia in a diverse population of 448 hyponatremic patients. Efficacy in a sub-set of 19 schizophrenic patients with idiopathic hyponatremia included in that sample is specifically examined.


      Nineteen subjects were randomly assigned to receive placebo (n = 12) or tolvaptan (n = 7) once daily for 30 days. Dosage adjustment was based on serum Na+ changes, initially 15 mg, titratable to 30 or 60 mg. The average daily area under the curve (AUC) changes in serum Na+ from baseline to Day 4 and Day 30 were co-primary end points.


      Increases in serum Na+ concentrations were significantly greater with tolvaptan than placebo at Day 4 (p = .0055) and at Day 30 (p < .0001). Two subjects receiving tolvaptan (28.6%) became dehydrated and experienced hypotension, and five subjects receiving placebo (41.7%) experienced symptoms associated with dilutional hyponatremia.


      These results suggest that tolvaptan effectively normalizes idiopathic hyponatremia in schizophrenic patients. Clinicians are advised to carefully monitor fluid status especially at the beginning of treatment to prevent dehydration.

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        • Hoskins R.G.
        Schizophrenia from the physiological point of view.
        Ann Intern Med. 1933; 7: 445-456
        • Targowla R.
        Des troubles fonctionnel du rein dans les maladies mentales.
        Bull Soc Med Hop Paris. 1923; 47: 1711-1715
        • Barahal H.S.
        Water intoxication in a mental case.
        Psychiat Quart. 1938; 12: 767-771
        • Vieweg W.V.
        • David J.J.
        • Rowe W.T.
        • Wampler G.J.
        • Burns W.J.
        • Spradlin W.W.
        Death from self-induced water intoxication among patients with schizophrenic disorders.
        J Nerv Ment Dis. 1988; 173: 161-165
        • de Leon J.
        • Verghese C.
        • Tracy J.I.
        • Josiassen R.C.
        • Simpson G.M.
        Polydipsia and water intoxication in psychiatric patients: A review of the epidemiological literature.
        Biol Psychiatry. 1994; 35: 519-530
        • Shutty Jr, M.S.
        • Briscoe L.
        • Sautter S.
        • Leadbetter R.A.
        Neuropsychological manifestations of hyponatremia in chronic schizophrenia patients with the syndrome of psychosis, intermittent hyponatremia and polydipsia (PIP).
        Schizophr Res. 1993; 10: 125-130
        • Bhardwaj A.
        Neurological impact of vasopressin dysregulation and hyponatremia.
        Ann Neurol. 2006; 59: 229-236
        • Renneboog B.
        • Musch W.
        • Vandemergel X.
        • Manto M.U.
        • Decaux G.
        Mild chronic hyponatremia is associated with falls, unsteadiness, and attention deficits.
        Am J Med. 2006; 119: 71
        • Delva N.J.
        • Crammer J.L.
        • Jarzylo S.V.
        • Lawson J.S.
        • Owen J.A.
        • Sribney M.
        • et al.
        Osteopenia, pathological fractures, and increased urinary calcium excretion in schizophrenic patients with polydipsia.
        Biol Psychiatry. 1989; 26: 781-793
        • Vieweg W.V.
        Treatment strategies in the polydipsia-hyponatremia syndrome.
        J Clin Psychiatry. 1994; 55: 154-160
        • Canuso C.M.
        • Goldman M.B.
        Clozapine restores water balance in schizophrenic patients with polydipsia-hyponatremia syndrome.
        J Neuropsychiatry Clin Neurosci. 1999; 11: 86-90
        • Wong L.L.
        • Verbalis J.G.
        Vasopressin V2 receptor antagonists.
        Cardiovasc Res. 2001; 51: 391-402
        • Udelson J.E.
        • Smith W.B.
        • Hendrix G.H.
        • Painchaud C.A.
        • Ghazzi M.
        • Thomas I.
        • et al.
        Acute hemodynamic effects of conivaptan, a dual V(1A) and V(2) vasopressin receptor antagonist, in patients with advanced heart failure.
        Circulation. 2001; 104: 2417-2423
        • Saito T.
        • Ishikawa S.
        • Abe K.
        • Kamoi K.
        • Yamada K.
        • Shimizu K.
        • et al.
        Acute aquaresis by the nonpeptide arginine vasopressin (AVP) antagonist OPC-31260 improves hyponatremia in patients with syndrome of inappropriate secretion of antidiuretic hormone (SIADH).
        J Clin Endocr Metab. 1997; 82: 1054-1057
        • Yamamura Y.
        • Nakamura S.
        • Itoh S.
        • Hirano T.
        • Onogawa T.
        • Yamashita T.
        • et al.
        OPC-41061, a highly potent vasopressin V2-receptor antagonist: Pharmacological profile and aquaretic effect by single and multiple oral dosing in rats.
        J Pharmacol Exp Ther. 1998; 287: 860-867
        • Hirano T.
        • Yamamura Y.
        • Nakamura S.
        • Onogawa T.
        • Mori T.
        Effects of the V2-receptor antagonist OPC-41061 and the loop diuretic furosemide alone and in combination in rats.
        J Pharmacol Exp Ther. 2000; 292: 288-294
        • Costello-Boerrigter L.C.
        • Smith W.B.
        • Boerringter G.
        • Ouyang J.
        • Zimmer C.A.
        • Orlandi C.
        • et al.
        Vasopressin 2 receptor antagonism augments water excretion without changes in renal hemodynamics or sodium and potassium excretion in human heart failure.
        Am J Physiol-Renal. 2006; 290: F273-F278
        • Schrier R.W.
        • Gross P.
        • Gheorghiade M.
        • Berl T.
        • Verbalis J.
        • Czerwiec F.S.
        • et al.
        Tolvaptan, a selective oral vasopressin V2-receptor antagonist, for hyponatremia.
        N Engl J Med. 2006; 355: 2099-2112
        • Weise W.J.
        • Rimmer J.M.
        • Hood V.L.
        Tolvaptan for hyponatremia.
        N Engl J Med. 2007; 356: 961
        • Alvelos M.
        • Ferreira A.
        • Bettencourt P.
        • Pimenta J.
        • Azevedo A.
        • Serrão P.
        • et al.
        Effect of saline load and metoclopramide on the renal dopaminergic system in patients with heart failure and healthy controls.
        J Cardiovasc Pharm. 2005; 45: 197-203